A family of proteins found on the surface of cells is known as the ATP-binding cassette (ABC) family of transmembrane proteins. Expression of these proteins affects the therapeutic accumulation of drugs in the central nervous system as well as in cancer cells and affects the absorption of therapeutic drugs by the gastrointestinal tract. This family of proteins includes, but is not limited to, the transmembrane ATP-dependent drug translocation protein P-glycoprotein (Pgp; Nooter, K. and Sonneveld, P. Leuk. Res. 1993 18:233-243; Biedler, J. L. Cancer Res. 1994 54:666-678; Kerbel et al. Cold Spring Harbor Symp. Quant. Biol. 1994 59:661-672; Broxterman et al. Curr. Opin. Oncol. 1995 7:532-540; and List, A. F. Leukemia 1996 10:937-942), also referred to as the Multi-drug Resistance Protein (MDR), whose over expression is associated with multi-drug resistance (Demolombe, S, and Escande, D. TIPS 1996 17:273-275); and multidrug resistance associated protein 2 or MRP2, BCRP, MRP1, and the chloride channel Cystic Fibrosis Transmembrane Conductance Regulator (CFTR).
Pgp is expressed in a variety of normal tissues including liver, kidney and colon and in tumors arising from these tissues that usually over express Pgp as part of their multi-drug resistance (MDR) phenotype (Cole et al. Science 1992 258:1650-1654; Roninson, I. B. Biochem. Pharmacol. 1992 43:95-102; Arceci, R. J. Blood 1993 81:2215-2222; and Merkel et al. J. Clin. Oncol. 1989 7:1129-1136). Pgp can also be over expressed in tumors from tissues that do not normally express this protein, such as breast and ovarian tissues (Arceci, R. J. Blood 1993 81:2215-2222; and Ihnat et al. Clin. Cancer Res. 1997 3:1339-1346). The mechanism of Pgp upregulation in tumors in vivo is still unclear, but can occur de novo as in acute myologenous leukemia (AML) (Gregorcyk et al. Ann. Surg. Oncol. 1996 3:8-14; Koh et al. Yonsei Medical Journal 1992 33:137-142; Dalton, W. S. and Sikic, B. I. J. NIH Res. 1994 6:54-58; Cole et al. Science 1992 258:1650-1654; Demolombe, S. and Escande, D. TIPS 1996 17:273-275; Schneider et al. British J. Cancer 1989 60:815-818; Fojo et al. Proc. Natl. Acad. Sci. USA 1987 84:265-269; Roninson, I. B. Biochem. Pharmacol. 1992 43:95-102; Arceci, R. J. Blood 1993 81:2215-2222; and Merkel et al. J. Clin. Oncol. 1989 7:1129-1136) or can be acquired over the course of cancer treatment as in breast and ovarian cancer (Merkel et al. J. Clin. Oncol. 1989 7:1129-1136; Ihnat et al. Clin. Cancer Res. 1997 3:1339-1346; Hamilton, J. W. and Wetterhahn, K. E. Mol. Carcinogens 1989 2:274-286; and McCaffrey et al. Mol. Carcinogens 1994 10:189-198).
MDR1 gene transcription and MDR1 mRNA expression can be induced by certain DNA damaging agents, including chemotherapeutic drugs such doxorubicin, alkylating agents such as methyl methanesulfonate, and genotoxic chemical carcinogens that induce bulky DNA adducts such as aflatoxin B1 and 2-acetylaminofluorene.
MRP1, MRP2, and BCRP are also members of the ABC family of transmembrane proteins involved in the transport of small therapeutic drugs and other molecules across cell membranes.
CFTR, another member of the ABC family of transport proteins is a cAMP-regulated chloride channel that mediates transepithelial chloride transport in the airways, intestine, pancreas, testis and other tissues. Cystic fibrosis, a lethal genetic disease, is caused by mutations in the CFTR gene, the most common of which is ΔF508. Intestinal CFTR contributes to the massive fluid and electrolyte losses in secretory diarrhea (Al-Awqati, Q. J. Clin. Invest. 2002 110(11):1599-601; Kunzelman et al. Physiol. Rev. 2002 82(1):245-89).
The ability to modulate the expression of these proteins has broad applications in a variety of clinical situations including, but not limited to, prevention of multidrug resistance in cancer, delivery of therapeutics to the central nervous system, inhibition of secretory diarrhea, and treatment of cystic fibrosis.